Immunogenicity, safety, and efficacy of rurioctocog alfa pegol in previously untreated patients with severe hemophilia A: interim results from a phase 3, prospective, multicenter, open-label study

Figures & data

Figure 1. Patient disposition. Of the 18 patients who did not meet the eligibility criteria, 1 was rescreened and entered with a different patient ID. Therefore, this patient was counted twice. FVIII, factor VIII; ITI, immune tolerance induction.

Table 1. Patient demographics and baseline characteristics.

	All patients (N = 59)
Age at informed consent (months), mean (SD)^a	11.8 (8.2)
Male, n (%)	59 (100.0)
Race, n (%)
Asian	15 (25.4)
Black or African American	4 (6.8)
White	37 (62.7)
Other	3 (5.1)
Family history of hemophilia A, n (%)
Grandfather	7 (11.9)
Father^b	1 (1.7)
Uncle	11 (18.6)
Brother	11 (18.6)
Other^c	9 (15.3)
Family history of FVIII inhibitors, n (%)^d	1 (1.7)
Number of exposure days prior to screening, n (%)
0	36 (61.0)
1	9 (15.3)
2	14 (23.7)
Exposure days prior to screening^e, mean (SD)	0.6 (0.9)
Weight (kg), mean (SD)	10.3 (2.4)
Height (cm), mean (SD)	76.1 (9.7)
BMI (kg/m^2), mean (SD)	17.7 (2.3)
FVIII inhibitor at screening (BU), mean (SD)	<0.4 (0.0)
Hemophilia-associated gene mutations, n (%)
High risk	29 (49.2)
Large deletion	3 (5.1)
Intron 1 inversion	1 (1.7)
Intron 22 inversion	22 (37.3)
Substitution nonsense mutation	3 (5.1)
Low risk	21 (35.6)
Small deletion	5 (8.5)
Small duplication	8 (13.6)
Substitution-missense mutation	8 (13.6)
Unknown risk	4 (6.8)
Factor 8 gene: C5471dela, P.n1824fs 46	1 (1.7)
Hemizygous for C.2015–2017 Del Tct mutation	1 (1.7)
Exon 14 mutation	1 (1.7)
Splice site mutation	1 (1.7)
Mutation status unknown	5 (8.5)

^aAge at informed consent as reported on the electronic case report form, converted to months; ^bAlthough a patient cannot inherit a gene defect on the X chromosome (as with hemophilia A) from his father, 1 patient did have a father with hemophilia A (and either had a spontaneous mutation of the X chromosome or inherited a defective X chromosome from his mother); ^cFamily history of hemophilia A specified as ‘other:’ maternal first cousin, maternal third cousin, maternal great grandfather, maternal uncle, and maternal great uncle all for 1 patient; cousin for 3 patients, and grandmother’s grandfather and grandchildren for 1 patient; ^dFamily history of FVIII inhibitors specified as ‘other:’ cousin (1 patient); ^eExposure days prior to screening was defined as the unique calendar days that the patient received octocog alfa, fresh frozen plasma, or rurioctocog alfa pegol prior to screening.

BMI, body mass index; BU, Bethesda unit; FVIII, factor VIII; SD, standard deviation.

Table 2. Patients receiving rurioctocog alfa pegol with at least 1 positive post-baseline binding IgG and IgM antibody to FVIII, PEG-FVIII, and PEG.

		All patients (N = 59)
Year after first exposure^a	Binding antibody	Positive, n	Negative, n
0 years	IgG: FVIII	2	32
	IgM: FVIII	0	34
	IgG: PEG-FVIII	4	30
	IgM: PEG-FVIII	2	32
	IgG: PEG	0	34
	IgM: PEG	4	30
1 year	IgG: FVIII	7	26
	IgM: FVIII	0	34
	IgG: PEG-FVIII	32	2
	IgM: PEG-FVIII	3	31
	IgG: PEG	11	23
	IgM: PEG	3	31
2 years	IgG: FVIII	0	21
	IgM: FVIII	0	21
	IgG: PEG-FVIII	1	20
	IgM: PEG-FVIII	0	21
	IgG: PEG	1	20
	IgM: PEG	0	21
3 years	IgG: FVIII	0	6
	IgM: FVIII	0	6
	IgG: PEG-FVIII	2	4
	IgM: PEG-FVIII	0	6
	IgG: PEG	1	5
	IgM: PEG	0	6

^aNumber of years after first rurioctocog alfa pegol exposure in study (0 years: results prior to first exposure in study; 1 year: results from first exposure in study up to and including 1 year after first dose; 2 years: results after first exposure in study +1 year up to and including first exposure in study +2 years; 3 years: results after first exposure in study +2 years up to and including first exposure in study +3 years). The substrate for FVIII binding antibodies was recombinant FVIII (octocog alfa) and the substrate for FVIII-PEG binding antibodies was recombinant PEG-FVIII (rurioctocog alfa pegol).

FVIII, factor VIII; Ig, immunoglobulin; PEG, polyethylene glycol.

Table 3. Hemostatic efficacy of rurioctocog alfa pegol in prophylactic treatment and control of bleeds.

Category	All bleeds			Minor severity			Moderate severity
	On-demand(n = 113)	Prophylaxis(n = 156)	Total(N = 269)	On-demand(n = 55)	Prophylaxis(n = 84)	Total(N = 139)	On-demand(n = 47)	Prophylaxis(n = 60)	Total(N = 107)
Efficacy rating after 24 hours, n (%)
Excellent	27 (23.9)	31 (19.9)	58 (21.6)	15 (27.3)	11 (13.1)	26 (18.7)	6 (12.8)	17 (28.3)	23 (21.5)
Good	33 (29.2)	31 (19.9)	64 (23.8)	15 (27.3)	10 (11.9)	25 (18.0)	18 (38.3)	17 (28.3)	35 (32.7)
Fair	3 (2.7)	4 (2.6)	7 (2.6)	1 (1.8)	2 (2.4)	3 (2.2)	1 (2.1)	2 (3.3)	3 (2.8)
None	2 (1.8)	0	2 (0.7)	1 (1.8)	0	1 (0.7)	0	0	0
NA	21 (18.6)	29 (18.6)	50 (18.6)	14 (25.5)	18 (21.4)	32 (23.0)	6 (12.8)	10 (16.7)	16 (15.0)
NR	27 (23.9)	61 (39.1)	88 (32.7)	9 (16.4)	43 (51.2)	52 (37.4)	16 (34.0)	14 (23.3)	30 (28.0)
Efficacy rating at bleed resolution, n (%)
Excellent	42 (37.2)	46 (29.5)	88 (32.7)	26 (47.3)	21 (25.0)	47 (33.8)	10 (21.3)	22 (36.7)	32 (29.9)
Good	41 (36.3)	32 (20.5)	73 (27.1)	18 (32.7)	9 (10.7)	27 (19.4)	23 (48.9)	18 (30.0)	41 (38.3)
Fair	3 (2.7)	4 (2.6)	7 (2.6)	1 (1.8)	2 (2.4)	3 (2.2)	1 (2.1)	2 (3.3)	3 (2.8)
None	2 (1.8)	0 (0.0)	2 (0.7)	1 (1.8)	0	1 (0.7)	0	0	0
NR	25 (22.1)	74 (47.4)	99 (36.8)	9 (16.4)	52 (61.9)	61 (43.9)	13 (27.7)	18 (30.0)	31 (29.0)
	Major severity			Joint bleeds			Non-joint bleeds
Category	On-demand(n = 10)	Prophylaxis(n = 12)	Total(N = 22)	On-demand(n = 27)	Prophylaxis(n = 32)	Total(N = 59)	On-demand(n = 88)	Prophylaxis(n = 127)	Total(N = 215)
Efficacy rating after 24 hours, n (%)
Excellent	6 (60.0)	3 (25.0)	9 (40.9)	5 (18.5)	10 (31.3)	15 (25.4)	22 (25.0)	22 (17.3)	44 (20.5)
Good	0	4 (33.3)	4 (18.2)	6 (22.2)	4 (12.5)	10 (16.9)	28 (31.8)	27 (21.3)	55 (25.6)
Fair	1 (10.0)	0	1 (4.5)	1 (3.7)	1 (3.1)	2 (3.4)	2 (2.3)	3 (2.4)	5 (2.3)
None	1 (10.0)	0	1 (4.5)	1 (3.7)	0	1 (1.7)	1 (1.1)	0	1 (0.5)
NA	0	1 (8.3)	1 (4.5)	4 (14.8)	3 (9.4)	7 (11.9)	17 (19.3)	26 (20.5)	43 (20.0)
NR	2 (20.0)	4 (33.3)	6 (27.3)	10 (37.0)	14 (43.8)	24 (40.7)	18 (20.5)	49 (38.6)	67 (31.2)
Efficacy rating at bleed resolution, n (%)
Excellent	6 (60.0)	3 (25.0)	9 (40.9)	8 (29.6)	12 (37.5)	20 (33.9)	34 (38.6)	35 (27.6)	69 (32.1)
Good	0	5 (41.7)	5 (22.7)	8 (29.6)	6 (18.8)	14 (23.7)	34 (38.6)	27 (21.3)	61 (28.4)
Fair	1 (10.0)	0	1 (4.5)	1 (3.7)	1 (3.1)	2 (3.4)	2 (2.3)	3 (2.4)	5 (2.3)
None	1 (10.0)	0	1 (4.5)	1 (3.7)	0	1 (1.7)	1 (1.1)	0	1 (0.5)
NR	2 (20.0)	4 (33.3)	6 (27.3)	9 (33.3)	13 (40.6)	22 (37.3)	17 (19.3)	62 (48.8)	79 (36.7)

Efficacy was rated as follows: Excellent, full relief of pain and cessation of objective signs of bleeding after a single infusion. No additional infusion is required for the control of bleeding. Administration of further infusions to maintain hemostasis would not affect this scoring; Good, definite pain relief and/or improvement in signs of bleeding after a single infusion. Possibly requires >1 infusion for complete resolution; Fair, probable and/or slight relief of pain and slight improvement in signs of bleeding after a single infusion. Required >1 infusion for complete resolution; None, no improvement or condition worsens; Not applicable, refers to bleeds that were resolved within 24 hours after first infusion. These bleeds only have a rating at bleed resolution.

NA, not applicable; NR, not reported.

Table 4. Weight-adjusted consumption and number of infusions for patients receiving rurioctocog alfa pegol prophylaxis.

	Prophylaxis(n = 54)
Number of infusions per week, mean (SD)	1.2 (0.5)
Prophylactic dose per week (IU/kg), mean (SD)	54.5 (19.6)
Number of infusions per month, mean (SD)	5.3 (2.2)
Prophylactic dose per month (IU/kg), mean (SD)	239.7 (85.6)
Prophylactic dose per infusion (IU/kg), mean (SD)	45.8 (8.6)
Number of infusions required for bleed resolution, mean (SD)	1.3 (0.7)
Average total dose for bleed resolution^a (IU/kg), mean (SD)	60.5 (36.2)

^aAverage total dose for bleed resolution refers to the average of the sum of the doses of the infusions used for a given bleed until bleed resolution.

SD, standard deviation.

Table 5. Adverse events occurring during or after first dose of rurioctocog alfa pegol in the safety analysis set and patients who were subsequently enrolled to receive ITI.

	Patients who received ≥1 dose of rurioctocog alfa pegol		Patients who received ≥1 dose of rurioctocog alfa pegol for ITI
	Patients, n (%) (n = 59)	Number of events	Patients, n (%) (n = 5)	Number of events
AEs	52 (88.1)	283	4 (80.0)	17
Frequently reported AEs^a
Pyrexia	22 (37.3)	47	–	–
Upper respiratory tract infection	13 (22.0)	17	2 (40.0)	2
Nasopharyngitis	10 (16.9)	16	–	–
Factor VIII inhibitor development	10 (16.9)	10	–	–
Ear infection	8 (13.6)	18	–	–
Cough	8 (13.6)	10	–	–
Viral infection	6 (10.2)	7	–	–
All rurioctocog alfa pegol-related AEs (including SAEs)	12 (20.3)	13	1 (20.0)	1
SAEs	24^b (40.7)	32^b	3^c (60.0)	8^c
Rurioctocog alfa-pegol-related SAEs	9 (15.3)	9	1^d (20.0)	1
AEs leading to discontinuation of rurioctocog alfa pegol	5 (8.5)^e	15	0 (0.0)	0
AEs leading to discontinuation from study	3 (5.1)	9	0 (0.0)	0
Catheter-related AEs	1 (1.7)	2^f	1 (20.0)	2^f

^aReported in ≥10% of patients who received ≥1 dose of rurioctocog alfa pegol in the safety analysis set or >1 patient who received ≥1 dose of rurioctocog alfa pegol for ITI; ^bFactor VIII inhibitor development (10 events in 10 patients); hemarthrosis (3 events in 3 patients); pyrexia (3 events in 2 patients); gastroenteritis (2 events in 2 patients); bleeding (subcutaneous hematoma [2 events in 1 patient], and muscle hematoma, nail bed bleeding, pharyngeal hemorrhage, or unspecified hemorrhage [1 event in 1 patient each]); other SAEs (dyspnea, immune thrombocytopenia, irritability, mouth injury, road traffic accident, systemic viral infection, tachycardia, or tongue ulceration [1 event in 1 patient each]). One SAE of FVIII inhibitor development was not related to rurioctocog alfa pegol and instead was related to treatment with octocog alfa prior to infusion of rurioctocog alfa pegol; ^cVascular device infection (2 events) and tonsillitis, FVIII inhibitor development, mouth hemorrhage, muscle hemorrhage, pharyngeal hemorrhage, and device occlusion (1 event each); ^dThe onset date of this SAE occurred before the patient had enrolled to receive ITI. This patient received the first dose of ITI 20 days prior to receiving formal confirmation of inhibitor development by the central laboratory; ^eIncluding 2 instances of drug hypersensitivity and 3 instances of FVIII inhibitor development. The 2 instances of drug hypersensitivity resolved in both patients, rurioctocog alfa pegol was withdrawn and both patients discontinued the study. The 3 instances of FVIII inhibitor development included the patient who developed an inhibitor to octocog alfa, as well as the 2 patients who developed high-titer FVIII inhibitors to rurioctocog alfa pegol and did not enroll to receive ITI; therefore, the patients were considered to have completed the study; ^f1 patient experienced 2 catheter-related SAEs, both of which resolved.

AE, adverse event; FVIII, factor VIII; ITI, immune tolerance induction; SAE, serious adverse event.

Data availability statement

The datasets, including the redacted study protocol, redacted statistical analysis plan, and individual participants data supporting the results of the study, will be made available after the publication of study results within 3 months from initial request to researchers who provide a methodologically sound proposal. The data will be provided after its de-identification, in compliance with applicable privacy laws, data protection and requirements for consent and anonymization.